Antibodies against a key immune molecule leave people vulnerable to infections.

It's easy to forget just how busy our immune system normally is. But if your immune system is ever compromised, infections that we normally aren't even aware of suddenly become serious problems. The first reports of AIDS patients, for example, didn't necessarily note a massive immune failure; instead, they recorded a series of opportunistic infections and cancers that were normally only seen in people with compromised immune systems, such as patients undergoing chemotherapy.

That's why a series of cases in East Asia (mostly Thailand and Taiwan) was so confusing. The patients had made it well into adulthood without problems with infections, meaning there probably wasn't a genetic immune defect. Later in life, though, they began experiencing frequent and persistent infections, primarily caused by mycobacteria (specifically, relatives of tuberculosis). The patients did not have an HIV infection, and were not at any obvious risk of immune disorder. All of this indicated a new form of acquired immune deficiency, and some preliminary data suggested a problem with a signaling molecule used by the immune system.

Now, researchers have found strong evidence that the problem comes from signaling by interferon-γ, a key mediator of responses to surface infections. The molecule itself is produced normally; instead, the patients with immune deficiencies have developed antibodies that block its activity.

These results were hinted at by earlier case studies, but the new one enrolled over 200 patients, broken down into several groups: two groups with opportunistic infections, two with tuberculosis, and a group of healthy individuals. Blood samples were taken from each of them, and the researchers tested the activity of a variety of immune signaling molecules.

Most of the signaling molecules were perfectly normal. In the case of interferon-γ, the molecule was present but appeared to be incapable of signaling in the patients with opportunistic infections. If serum from these patients was mixed with the interferon-γ from a normal patient, it was able to inactivate it. All of which suggests that the patients' blood contains an external factor that inactivates this key signaling molecule.

The previous work had suggested antibodies were the culprit. And, indeed, the authors detected them with high frequency. Among the two groups suffering opportunistic infections, 81 and 95 percent of the patients had antibodies that could attach to interferon-γ and prevent it from doing anything useful.

Thus, in these patients, the immune system can respond normally to detecting infection, but the response ends up blunted, since one of its key components, interferon-γ, is never sensed by the cells intended to receive it.

How are these people ending up with antibodies directed against their own immune system? The authors speculate that it's a mix of genetic predisposition and some environmental factor. The patients they've found so far all have ancestors from East Asia, which supports the idea of a genetic predisposition. And they have all been living in the two countries where the patients were recruited, indicating they were likely to come into contact with an environmental factor that is geographically limited.

As for what's triggering the production of these antibodies, however, the researchers don't even have enough information to speculate. They do suggest, however, that targeting the antibodies could provide a valuable therapy. And that could be critical, given that standard treatments for these infections aren't clearing them in the absence of a functional immune system.